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MS. STEINSCHNEIDER: Thank you. Good morning. As Dan said, I am going to be presenting the regulatory background. It is the background against which FDA undertakes its risk management activities and it is the background for the scientific and veterinary practice questions that the VMAC will consider today.

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The starting point is the Food, Drug, and Cosmetic Act. The Food, Drug and Cosmetic Act is a national consumer protection law which regulates food, drugs and other therapeutic products for humans and other animals. It is implemented by the Food and Drug Administration, and the Food and Drug Administration is divided into centers, so the Center for Veterinary Medicine regulates all products for animals, whether that is food, drugs, devices.

On the human side, things are divided up a little bit more, and I may -- we will probably make reference to the Center for Drug Evaluation and Research which regulates drugs for -- intended for humans, but which may also be used by animals, and also the Center for Drug Evaluation and Research has a lot of experience as well with risk maps.

The Food, Drug and Cosmetic Act has a number of goals for drug products and this applies equally to humans and to drugs for humans and drugs for animals. The goals are that the drugs, marketed drugs, be safe and effective and that the labeling for the drugs is accurate and informative.

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Now, the FDCA gives us particular authorities to achieve those goals. As Dr. McChesney said, we can’t just do whatever makes sense, but we have to operate within this framework.

So, in general, we have oversight over the sort of the chemical substance of the drug in the way it is manufactured. We have oversight over the information that accompanies it, and that would be the labels. You will hear the reference to labels, which is the information that is actually on the drug or the package; labeling, which is information that is not attached but may come with it or be part of the sale of the drug even if physically separate.

Then, and next, we have oversight over both labeling and labels for over-the-counter drugs and prescription drugs. We also have oversight over advertising for prescription drugs. Lastly, our authorities extend to the questions of drug approval, whether a drug can be marketed at all.

I am going to discuss each one of these in turn, but as a general comment, it is important to understand that the FDA doesn’t directly regulate the practice of veterinarians or physicians.

If you look at those authorities -- drug manufacturing, drug information, information that goes with the drug, whether the drug can be marketed -- all relate to the firms who make them, the firms who distribute them, but the agency actions do affect what drugs are available to practitioners and the circumstances in which they may be used, so it is sort of an indirect regulation of practice, but not a direct regulation of practice, which is an indirect impact on practice.

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So to start with the questions that relate to the drug manufacturing, the substance of the drug, a drug’s safety obviously depends on, and its safety and effectiveness depends on how well the drug is made. The -- so the Food, Drug and Cosmetic Act sets out a number of violations of the Act that relate to manufacturing, and these come under a category that is called “Adulteration.”

There are a number of things that can make a drug adulterated, but, in general, a drug will be adulterated if it has some sort of kinds of defects in its substance, if it doesn’t have the quality, the identity, the strength, the purity it says it is supposed to have.

But it is impossible to test every drug that goes out on the market for whether there is a defect in the substance, so the Food, Drug and Cosmetic Act also says that drugs are adulterated if the process for manufacturing them is defective. So we look very closely and carefully at, what is the process for manufacturing a drug product? And whether the process is likely to insure the quality of that product.

Drug safety and effectiveness is also maximized when the information about the drug is accurate, complete and not misleading.

The FDA doesn’t fully separate the question of the substance from the information that goes with it; it is all part of one sort of package. And we -- there are a number of violations in the law that relate to when the information is problematic, those come under the category that is called “Misbranding.”

In general, again, summarizing a lot of provisions of the law, a drug will be misbranded if its labeling is false or misleading either because of what it says or in many cases what it fails to say. So you have to tell the truth about your drug product; you also can’t leave important stuff out.

Also, the drug will be considered misbranded if it fails to include information in the label or labeling that is required by the law or by our implementing regulations.

Labeling for prescription animal drugs is aimed at enabling a veterinarian to use the drug safely for its intended purpose. So, the labeling will identify a drug’s ingredients, the dosages, the indications, the target species, the frequency of the method of administration, the hazards, the contraindications, the side effects and the precautions. This is what we call “Conditions of Use” for the drug. And all of that is aimed at -- is designed to enable the veterinarian to use the drugs, animal drugs, safely. And also, drugs for food animals and food withdrawal times that protect humans by preventing drug residues in edible tissues of products.

Lastly, the third major component of our authority relates to the oversight over drug approval. Drug approval involves pre-market review by FDA of the evidence supporting a drug’s use, and that is designed to keep ineffective, unsafe, unproven drugs off the market.

In general, animal drugs must be approved by the FDA to be lawfully marketed. And to obtain approval of a drug, a firm, who is typically -- may be called the “Sponsor” or the “Applicant,” will file a New Animal Drug Application, NADA for short, with the proposed labeling and with a lot of information.

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The information is intended to show a number of things. First, that the drug is safe and effective under the Conditions of Use identified in the labeling. It doesn’t have to be safe and effective under every conceivable use, but under the uses as it is described in the labeling.

Also, the New Animal Drug Application comes with information about manufacturing methods, because we look to see if the manufacturing methods and controls are designed -- will assure the drug’s quality. It comes with the -- the application comes with proposed labeling because, again, we are reviewing it, doing a pre-market review, to insure that it is not false or misleading. And we also look at information to show whether it is for a food-producing animal, whether the drug -- to insure that it doesn’t result in unsafe residues in foods.

We also have, as they do on the human side, generic drugs, which are essentially copies of an already approved drug, and these are -- come under the -- I think of “Abbreviated New Animal Drug Application.” But they are all approved applications.

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Once a drug is approved, that means a firm can market it lawfully and that a veterinarian -- it also means that the drug must be used under the conditions as described in the labeling, except that veterinarians in general may use what is called “Extra Label,” differently than the conditions in the labeling, if the veterinarian has what is called a valid client/patient relationship. So, in general, if you are not a veterinarian, you have to use it exactly the way the label says, but veterinarians can prescribe Extra Label in appropriate circumstances.

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Now, all drugs have risks, so the safety that is required for FDA approval of a drug isn’t absolute. Rather, what we look is whether there is an appropriate balance of risk and benefit. And this was summarized by the Center for Drug Evaluation and Research, by CDER, on the human side very nicely: “A drug is safe if the clinical significance and probability of its beneficial effects outweigh the likelihood and medical importance of its harmful or undesirable effects.”

So again, we are looking at whether the benefits of the drug justify any safety risks associated with the drug, and, again, that is under the Conditions of Use as stated in the labeling.

So to address drug safety issues, FDA uses the term “Risk Management,” which refers to a number of strategies and activities that really relate to two items, risk assessment and risk minimization. Obviously, you can’t minimize a risk until you know what it is.

The routine method for risk minimization applicable to every drug approved by the agency is the professional labeling. It communicates to the practitioner, the prescriber, what they need to know, what we know about how to use the drug safely. So that is the sort of the routine way we minimize risk, is by providing appropriate information in the labeling.

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For risk assessment, Dr. McChesney described our adverse event reporting system. By monitoring the adverse events, we can monitor not only risks that we already know about but any that emerge once the drug goes on the market.

There are standard requirements for reporting which can be modified by the FDA, but in general describe the people who hold the applications are responsible to report adverse events that are reported to them by practitioners, consumers, whoever may report to them.

Serious, unexpected adverse events have to be reported fairly quickly. “Unexpected” means if it is not reflected in the labeling and others at more -- at lengthier intervals. And again, professionals and consumers may voluntarily report adverse events to the FDA.

So that is the sort of standard adverse event reporting model. And again, an adverse event isn’t something where the firm -- they don’t report whether they conclude that the drug caused the problem; they report the event to us and we assess whether there is a link between the two.

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But it turns out that some drugs have risks that are either unusual in the type of level of risk coupled with unusual benefits, so that presents a problem for the FDA, or a challenge. And when a drug is found to have these unusual risks, the first step is to make changes in the professional labeling and to enhance the adverse event reporting requirements by application holders to try and minimize the risk and understand the risk.

But sometimes that is not enough, and additional approaches may be needed, and that is where RiskMAPs come in. RiskMAPs were developed basically to improve the risk/benefit ratio of drugs with special safety risks. So if you change the conditions of use, you can minimize some of the risks while maximizing the benefit.

Now, I will say that very often RiskMAPs are thought of as restricting access to drugs, which I understand that is how it can feel to practitioners and to people who need to access the drugs.

But looked at from a different point of view, RiskMAPs actually maintain access to drugs because given the risk of these products, they might not otherwise be able to be marketed, they might not meet the standard for approval. So in that sense, a RiskMAP actually increases access to drugs rather than decreasing it, although I realize it doesn’t necessarily feel that way.

So as I mentioned, RiskMAPs have been implemented for a number of human drugs and for the one veterinary drug that we will be discussing today.

RiskMAPs use a variety of tools or strategies to try and reduce risks. And I am going to just briefly run through the different categories as these were actually sort of defined by our counterparts at the Center for Drug Evaluation and Research for purposes of just thinking about all the options out there.

We divided them into three categories. But it is important to remember that a RiskMAP may combine tools from more than one category, as appropriate. And it is also important to remember that sponsors may develop other mechanisms than the ones I may mention here to address the particular risks of their drugs and the goals of their RiskMAP.

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So the first category of RiskMAP tools are -- it is called “Targeted Education and Outreach.” And basically these are communication programs that are intended to convey information about the drug’s risks and how to reduce those risks. In some cases, the information is specifically designed for healthcare professionals, for veterinarians and physicians, and examples of that might include a letter sent out to healthcare practitioners explaining the issues of the drug and how to use it, maximize its use, its safe use.

There can also be product-focused continuing education or communications through appropriate professional societies, professional venues, and of course websites targeted towards professionals because the Internet is terribly convenient for a lot of people.

On the other side, you may also have information that is specifically designed not for practitioners but for patients or clients so that they too can understand the risks and understand what they need to do to maximize the safe use of the drug at their end.

On the human side, there is -- if it is a written information, it will be called a “Medication Guide.” On the veterinary side, they are called “Client Information Sheets.” And when our drug has one of these, that should be provided to you regardless of whose -- of how it is dispensed. You should be getting some Medication Guide or the Client Information Sheet.

Again, there are also targeted websites for -- specifically designed for consumers, for patients or animal owners, to convey the risks, and that is another way of accessing the information. And it is also possible to utilize advertising the highlights of products’ risks.

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The second two systems are actually sort of connected, but we will sort of separate them out.

The second set of system is called “Reminder Systems,” and they really involve strategies or measures that are designed to -- that go sort of beyond just giving people information, that is designed to encourage the prescribing of the product, the dispensing of the product, or the use of the product in ways that reduce the risks.

So, for instance, you can have patient/client consent forms where not only is the patient -- are you given information, but you actually sign something to say you have looked at the materials and you understand the risk. It is sort of a way of underscoring what is in the informational material. On the practitioner side, there can be training programs that actually involve some kind of testing or other way of documenting that -- the provider’s knowledge as to the drug.

Then there are systems, or records, that sort of attest to the idea that certain safety measures were satisfied. For instance, prescribers may be told to put a sticker on the prescription to show that they have done whatever was needed to be done. Or they may be asked to formally attest to “These are the capabilities that are needed to reduce the risk of this drug if it is used and I have those capabilities.” Again, it is a way of underscoring how to use the drug safely.

Sometimes, providers, pharmacies or patients may be enrolled in data collection systems related to the drug, and that also gives a chance to reinforce the safe product use, as does if you limit the number of doses or refills on a drug, if you are on the receiving end of the drug, you are getting it either for your animals or for yourself, if you have to go back to your provider to get your prescription, that is another chance to have the risks underscored for you and the ways to use the drug properly.

Lastly, sometimes there are some -- there have been some cases where products have been put in special packaging to encourage safe use. That has been particularly the case where you have had drugs that might be particularly attractive to children but very dangerous, so it is really put in really very special packaging designed to keep the children away from the drug, some -- particularly drugs dispensed in sort of a -- what would look like a candy to a child, but in fact isn’t.

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Lastly, and this is what people might think of as the most restricted type of distribution, our performance-linked system. A performance-linked system directly limits the prescribing, dispensing or use of the drug, and it limits -- the limits are designed to make sure that the drug is used in populations that minimize the risk and maximize the benefits or that the conditions of use have been met that are designed to reduce the risks and maximize the benefits.

So an example of this is that the reminder system is mandatory. That sticker that has to go on the prescription? It has to go on the prescription, and the pharmacy won’t dispense without it.

Examples of some of the things you may be -- they may be attesting to with that sticker is that, for instance, these -- for instance, lab test results. So you might have a drug that has a lot of liver toxicity associated with it and the Condition of Use is that periodically liver tests, liver serum tests, are done. Well, in order to dispense that, the pharmacist may have to have evidence that those tests have been done.

Another example would be drugs that cause fetal abnormalities. There may be systems in place where the drug will not be dispensed by the pharmacist until the pharmacist has confirmation that pregnancy testing has been done for a woman of child-bearing age to prevent the drug being used inadvertently by a woman who is pregnant and doesn’t know it at that point.

You also have limitations that relate to prescriptions only by specially certified practitioners who are certified that they have the skills, knowledge and understanding of how to use that drug. And you might also have the dispensing limited only to -- you can only access it through certain pharmacies. You may be able to only get the drug from the sponsor. That is designed to insure that everything that needs to be done to insure the safe use of the drug has been done. Or you might actually limit the use of the drug to certain settings where the use is the most appropriate, such as actually in a hospital.

So those are some of the options out there. Again, sponsors -- you know, you need -- when faced with a drug like this, a sponsor needs to sit down and think, what are the risks and how they can be minimized. And these are just examples of types of things that have been used in the past in RiskMAPs.

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Lastly, I wanted to briefly talk on the -- touch on the role of public participation in RiskMAPs.

The FDA believes that the evaluation of a RiskMAP’s success and adjustment of it is necessary as part of an ongoing risk management process. And in particular, this development and evaluation of RiskMAPs have involved the opportunity for public input. It has especially been through the advisory committee process. The advisory committee gives us a chance to hear from experts who can talk about, with their perspectives, on the effectiveness of the RiskMAPs; practitioners can tell us about the impact of the RiskMAP on how it is working in their practice, and the public can also have a chance to describe how the RiskMAP is impacting them.

So, that is why we are here today, and with that, I will turn it over to the next speaker.

DR. DUNHAM: Thank you very, very much, Janice. It is my pleasure now -- we will have a team-tag approach by Dr. Stephen Sutherland and Dr. Tatty Hodge from Pfizer who will give an overview of the background of ProHeart 6, an overview of heartworm disease, and pharmacovigilance. Dr. Sutherland?